Transdermal delivery of drugs provides many advantages over other administrative routes. A number of different transdermal delivery systems have been proposed for administering a wide variety of drugs or other active agents. For example, U.S. Pat. Nos. 3,598,122; 3,598,123; 4,379,454; 4,286,592; 4,314,557 and 4,568,343 all disclose basic transdermal systems.
Despite the development of the transdermal art, there has remained a continuing need for improved techniques and compositions for effective drug delivery. Often, the rate at which a particular drug or beneficial agent is absorbed by the skin is well below the rate necessary to provide a therapeutically beneficial effect. This is especially true of potent opioids, like hydromorphone and buprenorphine, which are useful as analgesics in the treatment of moderate and severe pain.
The analgesic activities of hydromorphone and buprenorphine are about 7 and 30 times more potent than morphine, respectively. Hydromorphone is currently available in various forms such as tablets, syrup, injectables and suppositories under the trade name, Dilaudid.RTM. through Knoll Pharmaceutical Corporation. Buprenorphine is currently available in an injectable hydrochloride form as a parenteral solution under the trade name, Buprenex.RTM. through Norwich Eaton Pharmaceutical Corporation. None of these forms currently provide for effective transdermal delivery of either hydromorphone or buprenorphine.
U.S. Pat. No. 4,626,539 discloses a method of administering an opioid to the systemic circulation of a mammal. The formulation disclosed consists of an effective amount of an opioid, a penetration enhancer, and a carrier vehicle. The enhancer includes at least one of a saturated fatty acid of 8-15 carbon atoms or of an unsaturated fatty acid of 8-18 carbon atoms. The carrier vehicle preferably includes propylene glycol which makes up 30-80% of the total formulation.
U.S. Pat. No. 4,615,699, discloses a reservoir-type transdermal delivery system for nitroglycerin at which an enhanced flux rate is obtained using ethanol as a permeation enhancer. The system includes a membrane for controlling the rate at which nitroglycerin leaves the system. The patent defines a transdermal delivery device as a system controlled when J.sub.net /J.sub.system .times.100.gtoreq.50%, where J.sub.net is the steady state in vitro drug input rate and J.sub.system is the in vitro steady state flux of the agent from the device directly into an infinite sink. This definition is based on the following relationship: ##EQU1## where J.sub.skin is the in vivo or in vitro steady state flux of the agent directly through skin from a unit activity solution.
U.S. Pat. No. 4,593,048 discloses skin penetration enhancers comprising a lower alcohol containing 1-4 carbon atoms and at least one adjuvant. One of the adjuvant candidates consists of an aliphatic carboxylic acid monohydric alcohol ester containing 19-24 carbon atoms in total wherein the carboxylic acid moiety is a fatty acid moiety containing 18 carbon atoms and the alcohol moiety contains 1-6 carbon atoms.
U.S. Pat. No. 4,588,580 discloses a process for transdermal delivery of fentanyl and its derivatives using ethanol as a permeation enhancer.
U.S. Pat. No. 3,952,099 discloses compositions for skin permeation enhancement comprising a sugar ester in combination with a sulfoxide or phosphine oxide.
U.S. Pat. No. 3,896,238 discloses skin permeation enhancers comprising at least about 0.1 wt. % of a sugar ester and at least about 0.1 wt. % of a sulfoxide of the formula R.sup.1 S(O)R.sup.2. The sugar ester is a member selected from the group consisting of sucrose monooctanoate, sucrose monodecanoate, sucrose monolaurate, sucrose monomyristate, sucrose monopalmitate, sucrose monostearate, sucrose monooleate and sucrose dioleate.
Hydromorphone and buprenorphine are known to have poor bioavailability due to extensive liver and intestinal metabolism. They can produce severe side effects, particularly respiratory depression on over dosage. It is therefore desirable to deliver these opioids non-orally and at a constant rate. Thus, it is an object of the present invention to provide transdermal delivery systems for drugs, particularly hydromorphone and buprenorphine, which can deliver the drug at therapeutically effective rates for extended periods of time. This objective is achieved by substantially enhancing the skin permeation of the drug and by adjusting the skin contact area of the transdermal delivery system.
Therefore, the present invention provides for transdermal delivery of drugs at therapeutically effective rates and offers the advantages of greatly increased drug permeability through the skin. Although it is known in the art to combine polar and non-polar components, the invention utilizes a novel combination of non-volatile components to achieve a combined synergistic effect which is a significant improvement and unexpectedly surprising in view of the use of either component, alone.
Other objects and advantages of the present invention will be apparent to those skilled in the art with reference to the attached drawings and the description of the invention which hereinafter follows.